WARNINGS AND PRECAUTIONS
See Table 3 for a listing of drugs that are contraindicated for use with REYATAZ (atazanavir sulfate) due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. [See Contraindications (4)
.] Please refer to Table 13 for established and other potentially significant drug interactions [see Drug Interactions
Cardiac Conduction Abnormalities
Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions
]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), atazanavir should be used with caution in these patients. [See Clinical Pharmacology
Atazanavir in combination with diltiazem increased diltiazem plasma concentration by 2-fold with an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one-half should be considered and ECG monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, no clinically significant additive effect of atazanavir and atenolol on the PR interval was observed. Dose adjustment of atenolol is not required when used in combination with atazanavir. [See Drug Interactions (7)
and Clinical Pharmacology
.] Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers [other than atenolol, see Drug Interactions (7)
], verapamil, and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A (eg, verapamil).
In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions
]. Dosing with REYATAZ (atazanavir sulfate) was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ. [See Contraindications (4)
Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times ULN. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established. [See Adverse Reactions (6.1, 6.2)
Caution should be exercised when administering REYATAZ to patients with hepatic impairment because atazanavir concentrations may be increased. [See Dosage and Administration
.] Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment. [See Adverse Reactions
and Use in Specific Populations
Nephrolithiasis and Cholelithiasis
Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered. [See Adverse Reactions .]
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. [See Adverse Reactions
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors. [See Clinical Pharmacology
USE IN SPECIFIC POPULATIONS
Pregnancy Category B
Antiretroviral Pregnancy Registry:
To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.
Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. All infants, including neonates exposed to REYATAZ in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
Dosing During Pregnancy and the Postpartum Period:
•No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery. [See Dosage and Administration (2, 2.3) and Clinical Pharmacology
•REYATAZ should not be administered without ritonavir.
•REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
•For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times the upper limit of normal). There were no cases of lactic acidosis observed in clinical trial AI424-182.
Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12-19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
Antiretroviral Pregnancy Registry Data:
As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.
Pharmacokinetics of Atazanavir in Pregnancy
[See Clinical Pharmacology
In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and post-natal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether atazanavir is present in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are taking REYATAZ.
REYATAZ should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus.
The safety, activity, and pharmacokinetic profiles of REYATAZ in pediatric patients ages 3 months to less than 6 years have not been established.
The safety, pharmacokinetic profile, and virologic response of REYATAZ were evaluated in pediatric patients in an open-label, multicenter clinical trial PACTG 1020A [see Clinical Pharmacology
and Clinical Studies
]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions
]. Please see Dosage and Administration
for dosing recommendations for pediatric patients 6 years of age and older.
Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; ≥65 years) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender.
Impaired Renal Function
In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age, weight, and gender matched subjects with normal renal function. Atazanavir was not appreciably cleared during hemodialysis. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25 to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Dosage and Administration
Impaired Hepatic Function
Atazanavir is metabolized and eliminated primarily by the liver. REYATAZ (atazanavir sulfate) has been studied in adult subjects with moderate to severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. The pharmacokinetics of REYATAZ in combination with ritonavir have not been studied in subjects with hepatic impairment. REYATAZ should not be administered to patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended for use in patients with hepatic impairment. [See Dosage and Administration
and Warnings and Precautions